This application is a 371 of PCT/GB00/04055, filed Oct. 20, 2000. The present invention relates to a class of novel chemical entities which act as agonists of the peptide hormone vasopressin. They reduce urine output from the kidneys and so are useful in the treatment of certain human diseases characterised by polyuria. They are also useful in the control of urinary incontinence and bleeding disorders.
Vasopressin is a peptide hormone secreted by the posterior pituitary gland. It acts on the kidney to increase water retention and so reduce urine output. For this reason, vasopressin is alternatively known as xe2x80x9cantidiuretic hormonexe2x80x9d. It also acts on the vasculature, where it produces a hypertensive effect. The cellular receptors that mediate these two actions have been characterised and shown to be different. The antidiuretic action is mediated by the type-2 vasopressin receptor, commonly called the V2 receptor. Agents that can interact with the V2 receptor and activate it in the same way as vasopressin are called V2 receptor agonists (or simply V2 agonists). Such agents will have an antidiuretic action. If these agents interact selectively with the V2 receptor and not the other vasopressin receptor subtypes, then they will not have the hypertensive effect of vasopressin. This would be an important safety consideration and make such agents attractive for the treatment of human disease conditions characterised by polyuria (which is herein taken to mean excessive urine production). 
In fact, such an agent is already in use in human therapy. Desmopressin (otherwise [1-desamino, D-Arg8]vasopressin, Minirin(trademark), DDAVP(trademark)) is a peptide analogue of vasopressin which is selectively an agonist at the V2 receptor. It is used in the treatment of central diabetes insipidus, which is a condition that results from defective secretion of vasopressin. It is also employed in the control of nocturnal enuresis and may also be of use in the control of nocturia. However, desmopressin is not an ideal agent in all respects. Even the best current syntheses of the agent are lengthy, and desmopressin is not amenable to the most convenient of purification techniques such as crystallisation. Consequently, desmopressin is relatively expensive. It has a very low oral bioavailability, and there is some variability in this parameter. 
Overall then, there exists a need for a selective vasopressin V2 receptor agonist that is easy to prepare and purify, and that has a high and predictable oral bioavailability. Such properties are most likely to be obtained with a non-peptide compound. These considerations have led other groups to investigate non-peptide vasopressin V2 agonists, and their results are disclosed in, for example, International Patent Applications WO97/22591, WO99/06403, WO99/06409, WO00/46224, WO00/46225, WO00/46227 and WO00/46228. The compounds disclosed in these documents are, however, less than ideal. In particular, they have poor oral bioavailability, probably due in part to their low aqueous solubility. The present invention provides compounds with improved solubility and bioavailability.
Besides its antidiuretic actions, desmopressin is used to increase the concentration in the blood of the coagulation proteins known as Factor VIII and von Willebrand factor. In the clinical context, this makes desmopressin useful in the treatment of haemophilia A and von Willebrand""s disease. Similar applications would be open to the non-peptide agonists of the present invention.
As disclosed herein, the present invention relates to a series of compounds that are non-peptide agonists of vasopressin and which are selective for the V2 receptor subtype. The compounds are described by general formula 1
wherein:
V is a covalent bond or NH,
X is selected from CH2, O and N-alkyl,
Z is either S or xe2x80x94CHxe2x95x90CHxe2x80x94,
R1 and R2 are independently selected from H, F, Cl, Br and alkyl,
R3 is selected from OH, O-alkyl and NR4R5,
R4 and R5 are each independently H or alkyl, or together are xe2x80x94(CH2)qxe2x80x94,
p is 0, 1, 2, 3 or 4, and
q is 4 or 5.
The invention further comprises pharmaceutical compositions incorporating these vasopressin agonists, which compositions are particularly useful in the treatment of central diabetes insipidus, nocturnal enuresis and nocturia.
The present invention comprises N-acyl tetrahydroazepine derivatives defined by general formula 1. 
In this formula, V represents an NH group or a covalent bond. X represents a methylene group (xe2x80x94CH2xe2x80x94), an oxygen atom (O) or N-alkyl. Z represents a sulphur atom (S) or a group xe2x80x94CHxe2x95x90CHxe2x80x94.
R1 and R2 are each independently selected from H, F, Cl, Br and alkyl groups.
R3 is selected from OH, O-alkyl and NR4R5.
R4 and R5 are each independently selected from H and alkyl groups. Alternatively, they may together be xe2x80x94(CH2)qxe2x80x94, where q is 4 or 5, such that together with the nitrogen atom to which they are attached they form a pyrrolidine or piperidine ring.
The integer p may take the values 0, 1, 2, 3 and 4. When p is 0, a covalent bond exists between V and the COR3 group. When p is 0 and V is a covalent bond then a single covalent bond exists between the two carbonyl groups.
As used herein, xe2x80x9calkylxe2x80x9d includes saturated hydrocarbon residues, linear or branched, with up to six carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, neopentyl and n-hexyl.
Certain compounds of general formula 1 are capable of forming salts with acids or bases. For example, compounds containing a basic nitrogen atom can form addition salts with mineral and organic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulphonic acid, citric acid and benzoic acid. Compounds containing acidic groups can form salts with bases. Examples of such salts include the sodium, potassium, calcium, triethylammonium and tetraethylammonium salts. Furthermore, compounds that have both acidic and basic groups can form internal salts (zwitterions). Insofar as these salts are pharmaceutically acceptable, they are included within the scope of the invention.
In a preferred embodiment of the invention, the group Z is xe2x80x94CHxe2x95x90CHxe2x80x94.
In another preferred embodiment of the invention, Z is S.
In another preferred embodiment of the invention, X is a methylene group CH2.
In another preferred embodiment of the invention, R1 is a hydrogen atom and R2 is a methyl group or a chlorine atom.
In another preferred embodiment of the invention, R1 is a methyl group or a chlorine atom and R2 is a hydrogen atom.
In another preferred embodiment of the invention, R3 is O-alkyl.
Particularly preferred compounds within the invention combine the features of these preferred embodiments.
Individual preferred compounds within the invention include (but are not limited to) the following:
1-(4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-methoxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-hydroxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(5-methoxy-5-oxopentanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-hydroxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(3-methyl-4-[N-(2-methylamino-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-dimethylamino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-methoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-amino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
4-(3-chloro-4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]benzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine,
5-(4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1,5-benzoxazepine,
1-(4-[N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine,
1-(4-[N-(3-methoxy-3-oxopropanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(3-ethoxy-3-oxopropanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(3-hydroxy-3-oxopropanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(4-hydroxy-4-oxobutanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(5-hydroxy-5-oxopentanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(3-methoxy-3-oxopropanoyl)aminomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(N-xe2x80x2-ethoxycarbonylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-isopropoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-tert-butoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(3-chloro-4-[N-(2-dimethylamino-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(3-methyl-4-[N-(2-(1-piperidino)-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(3-methyl-4-[N-(2-(1-pyrrolidino)-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(3-ethoxy-3-oxopropylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine, and
1-(4-[N-(3-hydroxy-3-oxopropylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
The compounds of the present invention can be prepared using methods generally known in the art. The compounds of general formula 1 can be considered to be composed of three linked fragments (A-C). 
The three fragments will generally be prepared separately and then combined at a late stage in the synthesis. Some instances of the various groups (particularly R3 and X) might be incompatible with this assembly and so will require the use of protecting groups. The use of protecting groups is well known in the art (see for example xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, T. W. Greene, Wiley-Interscience, 1981). Particular groups that may require protection are amines (protected as amides or carbamates) and carboxylic acids (protected as esters). For the purposes of this discussion, it will be assumed that such protecting groups as are necessary are in place.
The fragments A, B and C can be combined according to two strategies to give the compounds of formula 1. In the first, fragments A and B are linked to give a fragment corresponding to AB, which is then combined with fragment C. In the second, fragments B and C are linked to give a fragment corresponding to BC, which is then combined with fragment A. The chemistry involved in the condensation of fragment A with B, and that involved in the condensation of fragment B with fragment C, will be the same whichever strategy is followed.
Formation of Fragment AB
The nature of the Axe2x80x94B bond forming reaction depends on the identity of V. 
Here, {A} and {B} represent part structures of the fragments A and B respectively. The formation of amides by the reaction of acid chlorides with primary amines is well known. In general, the amine and the acid chloride are mixed in an aprotic solvent such as dichloromethane or dimethylformamide in the presence of a tertiary amine such as triethylamine. 
The formation of ureas by the reaction between an isocyanate and a primary amine is also well known. In general, the amine and the isocyanate are mixed in an aprotic solvent such as dichloromethane or dimethylformamide. The presence of a tertiary amine such as triethylamine may be beneficial, but is generally not necessary. 
Formation of the amide bond between fragments B and C can be most easily achieved by allowing the acid chloride corresponding to fragment B to react with the secondary amine that is part of the azepine ring of fragment C. The reaction proceeds in an aprotic solvent in the presence of a tertiary amine base. Depending on the exact nature of the two fragments, this reaction may require more or less time to achieve satisfactory yields of the product. Alternatively, the carboxylic acid corresponding to fragment B may be condensed with the azepine using one of the many reagents known in the art to effect such amide bond forming reactions.
Overall then, the following intermediates are required for the synthesis of the compounds of the present invention.
i) For Fragment A 
Acid chlorides are well known. Many are items of commerce or described in the literature. Where the necessary acid chloride is not a known compound, it will generally be available in a single step from the corresponding carboxylic acid. Isocyanates are also well known. In general, they can be prepared from the corresponding primary amine by reaction with phosgene or an equivalent reagent.
ii) For Fragment B 
Because the primary amine and acid chloride groups are incompatible, they must be developed separately and protected. The acid chloride can be elaborated from the corresponding carboxylic acid, which is conveniently protected as its methyl ester. The primary amine can be elaborated from the corresponding nitrile (by reduction) or the alcohol (by displacement with a nitrogen nucleophile). The best method will depend on the nature of the substituents R1 and R2.
iii) For Fragment C 
Fused azepines of this type are prepared according to the methods described in the literature.
The present invention further comprises pharmaceutical compositions that include at least one compound according to the foregoing description as an active constituent. The composition may also include a second pharmacological agent such as a spasmolytic or a potassium channel blocker, these agents being known in the art to ameliorate bladder dysfunction. Preferably, the composition includes only one active constituent. The composition will include excipients selected from binding agents, bulking agents, dispersants, solvents, stabilising agents and the like, such excipients being generally known in the art.
The excipients used will depend on the intended nature of the formulation, which will, in turn, depend on the intended route of administration. Administration may be oral, transmucosal (such as sublingual, buccal, intranasal, vaginal and rectal), transdermal or by injection (such as subcutaneous, intramuscular and intravenous). Oral administration is generally preferred. For oral administration, the formulation will be a tablet or capsule. Other formulations include dry powders, solutions, suspensions, suppositories and the like.
In a further aspect, the present invention is a method of treating or controlling certain human physiological dysfunctions. This method comprises the administration to the person in need of such treatment of an effective amount of a pharmaceutical composition, which composition contains a compound according to the foregoing description as an active constituent. The compounds act to reduce urine output, and so the method of the invention can be applied to all conditions in which elevated urine output is a contributory factor. The compounds also increase the production of the blood coagulation proteins known as Factor VIII and von Willebrand factor, and so the treatment of bleeding disorders can be undertaken.
In a preferred embodiment, the condition treated is diabetes insipidus. This is a condition caused by an inability of the body to produce and secrete physiologically active vasopressin, with the result that water re-uptake is greatly reduced and large volumes of urine are produced.
In another preferred embodiment, the condition treated is nocturnal enuresis. This is defined as bladder emptying while the individual is sleeping. It is a condition that mainly affects children and a number of factors may be involved in its etiology.
In another preferred embodiment, the condition treated is nocturia. This is defined as production of sufficient urine during the night to require the individual to wake and empty his (or her) bladder. Again, this condition may be the result of a number of factors.
In another preferred embodiment, the condition treated is incontinence. This condition is characterised, in part, by reduced bladder capacity and control such that involuntary urination occurs unless the bladder is emptied frequently. Incontinence has been divided into two conditions, stress incontinence and urge incontinence. A number of etiological factors are thought to be involved. Treatment according to the invention is particularly useful for delaying the need for bladder emptying (xe2x80x9cvoiding postponementxe2x80x9d) in order to allow the incontinent subject a dry period of a few hours (such as up to four hours). Such voiding postponement may also be useful for the non-continent population, for example for people obliged to remain in meetings for extended periods.
In another preferred embodiment, the condition treated is haemophilia A or von Willebrand""s disease. These are conditions in which Factor VIII or von Willebrand factor production is reduced and the individual suffers from prolonged bleeding.
In another preferred embodiment, the composition is administered prior to surgery (including dental surgery) to increase the coagulability of the blood and so reduce peri-operative blood loss.
The administration of the compositions of the present invention will generally be under the control of a physician. The physician will determine the amount of composition to be administered and the dosing schedule, taking into account the patient""s physical condition and the therapeutic goals. For an adult diabetes insipidus patient, a typical dose might be between 50 mg and 1 g of the active compound per day, taken as a single tablet or as up to four tablets throughout the day. For routes of administration other than the oral route, the amount of compound will be reduced, since non-oral routes tend to be more efficient in terms of delivering therapeutic agents into the systemic circulation. For the treatment of haemophilia A and von Willebrand""s disease the amount of compound may need to be higher than for the treatment of diabetes insipidus.